The opioid receptor endorphin system consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types located in anatomically well defined areas of the mammalian CNS with the numerous endogenous opioid peptides (endorphins) which subserve these receptors. These receptors have been cloned and convincing pharmacological evidence now supports at least two subtypes of each. These results present many opportunities for research highly relevant to drug abuse and for the development of new medications that act on these receptors. The opioid receptor endorphin system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state including regulation of dopamine (DA) levels in the nucleus accumbens (NAC) and expression of the effects of alcohol. This system is dysregulated by the abuse of heroin, cocaine and prescription narcotics and the abuse of these drugs is presently an enormous problem. The abuse of prescription narcotics alone, especially oxycodone (oxycontin) surged 308% during 2000-2005 with 9.5% of twelfth grade students in 2004 having abused prescription narcotics within the last year.[unreadable] [unreadable] Recently however, encouraging studies have shown that moderately selective delta opioid antagonists suppress (a) cocaine seeking behavior, (b) heroin self-administration and (c) the development of tolerance and dependence to the mu agonist morphine. The former two observations strongly indicate that highly selective delta receptor antagonists might be valuable medications for the treatment and prevention of human cocaine and narcotic abuse and perhaps other undesirable reinforcing behaviors. The latter observation suggests that a drug showing a mu agonist-delta antagonist profile might produce strong analgesia without producing tolerance and dependence thus allowing continuous treatment of chronic pain. Animal studies with peptide-nonpeptide hybrid molecules (peptoids) have validated this hypothesis. These molecules showed strong analgesia with substantially reduced tolerance and dependence relative to morphine but are only effective when administered directly into the brain. We have experimental evidence that delta opioid agonists may be useful antidepressants and can also enhance immune function. In addition, kappa opioid antagonists have recently been found to have antidepressant-like activity and prevent stress-induced relapse in a rat model of cocaine self-administration. The exploitation of these and other similarly intriguing observations now requires novel, exquisitely selective, nonpeptide ligands as research tools and potential medications. These new tools will enable the study of many questions of fundamental importance concerning the function of mu, delta and kappa opioid receptor subtypes and how drugs interact with their receptors to elicit these functions. We have continued to design, synthesize and evaluate novel drugs for this purpose during the reporting period. The 5-phenylmorphans are a particularly interesting class of opioid receptor agonists that were originated by Everette May at NIH in 1955. We recently identified a mu agonist-delta antagonist and a delta inverse agonist in this series. Very few nonpeptide opioids in any structural class with this profile are known. We also reported another mu agonist-delta antagonist and an exceedingly potent mu agonist in this series. The latter is by far the most potent 5-phenylmorphan agonist known showing more that 1000 times the potency of morphine in the single dose suppression of morphine abstinence assay. The diverse profiles obtained in this series illustrate the importance of subtle changes on the carbon-nitrogen skeleton and careful attention to stereochemical detail and provide important leads toward pain medications with reduced side effects.[unreadable] [unreadable] Our studies in the role of stress in drug abuse have continued. We and others have shown that stress can play an important role in promoting drug self-administration and relapse to drug abuse. The corticotropin releasing hormone receptor (CRHR1) plays a central role in initiation of the response to stress. We showed that the CRHR1 antagonist antalarmin reduced ethanol self-administration in ethanol-dependent rats after acute ethanol withdrawal but not in ethanol nondependent rats. In related study, we found that antalarmin attenuated yohimbine stress induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Finally, we showed that spontaneous ethanol self-administration of nondependent Sardinian alcohol-preferring rats was suppressed by the opiate antagonist naltrexone and therefore opioid dependent. The CRHR1 antagonist LWH-63 reduced withdrawal-induced drinking in these rats but not spontaneous drinking in nondependent rats suggesting opioid and CRHR1 receptors play different roles in ethanol reinforcement. These studies suggest that CRHR1 antagonists may be useful in the treatment of human alcohol dependence in conjunction with naltrexone and that optimal treatment may vary between different subtypes of patients. [unreadable] [unreadable] The abuse of methylenedioxymethamphetamine (MDMA) and related hallucinogenic drugs is another serious problem. Recent data from the Drug Enforcement Administration show the appearance of novel hallucinogenic phenethylamines and tryptamines either previously encountered in insignificant amounts or not seen at all. This is due in part to the recent publication of cookbook chemical syntheses and detailed accounts of the doses used and hallucinogenic effects seen in humans for almost all of the 179 phenethylamine and 53 tryptamine analogs that were synthesized and self-administered by A. T. Shulgin and his associates during more than 30 years. These are disturbing developments that substantially aid and encourage clandestine drug production and may presage a resurgence in hallucinogenic drug abuse. We have begun a program to synthesize and evaluate a number of hallucinogenic agents and their antagonists. We developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907, its carbon-11 precursor for positron emission tomography and their enantiomers. We have studied the discriminative stimulus effects of several of these drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. Our results show that the 5-HT2A receptor is involved in psilocybin-induced stimulus control in rat. This receptor was also found to play a major role in the agonist action of N,N-dipropyltryptamine with a possible contribution of the 5-HT1A receptor.[unreadable] [unreadable] Lastly, we reviewed (a) the potential uses of corticotropin-releasing hormone antagonists and (b) the structure-activity relationships of biogenic amine reuptake inhibitors (potential cocaine and methamphetamine treatment agents) during the reporting period.